Serotonin transporter gene promoter methylation in peripheral cells in healthy adults: Neural correlates and tissue specificity

Eur Neuropsychopharmacol. 2017 Oct;27(10):1032-1041. doi: 10.1016/j.euroneuro.2017.07.005. Epub 2017 Jul 31.


Early adversity can influence gene expression via epigenetic mechanisms, including DNA methylation. Peripheral tissues are essential in psychiatric epigenetics, as methylation generally cannot be assessed in the living human brain. Several magnetic resonance imaging (MRI) studies show associations of peripheral serotonin transporter gene (SLC6A4) methylation with function and/or structure of frontal-limbic circuits and brain's resting-state. Commonly used samples are derived from blood, saliva or buccal cells. However, little is known regarding which peripheral tissue is most strongly associated with human brain processes. The aim of the current study was to compare the extent of the association between peripheral SLC6A4 promoter methylation and frontal-limbic function, structure and resting-state in healthy individuals across peripheral tissues. Forty healthy prospectively-followed adults underwent anatomical, resting-state and functional MRI. Saliva-, blood- and buccal-derived DNA methylation was assessed by pyrosequencing. Blood-derived SLC6A4 methylation was positively associated with superior frontal gray matter (GM) volume and with right lateral parietal area (RLP)-frontal pole regional resting-state functional connectivity (rsFC). Saliva-derived SLC6A4 methylation was positively associated with superior frontal GM volume. Buccal-derived SLC6A4 methylation was positively associated with superior and inferior frontal and anterior cingulate cortical (ACC) GM volumes, and with RLP-ACC, frontal pole and medial prefrontal regional rsFC. Current results confirmed the relevance of peripheral methylation for frontal-limbic processes in humans. Buccal cells may be the most sensitive cell type when studying SLC6A4 promoter methylation and its associated risk for neural vulnerability and resilience for psychopathologies in which serotonin is implicated. These data should be further validated in clinical populations.

Keywords: DNA methylation; Frontal cortex; Functional magnetic resonance imaging; Resilience; Serotonin transporter.

MeSH terms

  • Adult
  • Brain Mapping
  • Cheek
  • DNA Methylation*
  • Epithelial Cells / metabolism
  • Female
  • Follow-Up Studies
  • Frontal Lobe / diagnostic imaging
  • Frontal Lobe / physiology*
  • Gray Matter / diagnostic imaging
  • Gray Matter / physiology
  • Humans
  • Limbic System / diagnostic imaging
  • Limbic System / physiology*
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Parietal Lobe / diagnostic imaging
  • Parietal Lobe / physiology
  • Promoter Regions, Genetic*
  • Prospective Studies
  • Rest
  • Saliva / metabolism
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*


  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins